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2023年8月7日 星期一

201008250609 手指腳趾甲床及指甲外傷 Fingertip and Nailbed Injuries

上傳進度:已上傳 710990 個位元組 (共 710990 個位元組)。

甲床撕裂傷縫合之後. 需要把指甲種回去嗎? 在 Tintinalli教科書有圖片. 如何將甲床種回去. 要精確放入 eponychium 之下. 以保護指甲生長的起點 matrix.

An avulsion or crush injury may tear the nail completely away from the digit or raise a flap of nail bed matrix. Often fragments of matrix tissue may be left on the underside of the avulsed nail; these should be preserved for use as free grafts and, when possible, attached to the nail bed using fine 7-0 absorbable sutures. When the nail or avulsed nail bed fragments are not available, or in the case of a large defect, a full-thickness nail bed graft can be harvested from the patient's toe and sutured into the nail bed of the affected finger. As these injuries are complex and their repair is technically challenging, consultation with a hand or plastic surgeon is appropriate. In addition, avulsion injuries to the nail bed have the poorest prognosis of any fingertip injury. Avulsion injuries may also incompletely tear the proximal portion of the nail bed or the germinal matrix, normally located under the eponychium. When this happens, the germinal matrix may lie on top of the eponychium. Management entails replacement of the matrix into its anatomic position using a series of three horizontal mattress sutures (Fig. 39-3). One suture is placed through the center and one in each corner of the eponychial fold. The sutures are then passed through the proximal portion of the corresponding segment of avulsed germinal matrix and then back out through the nail fold, pulling the matrix back to its anatomic position.








Nail Bed Avulsion Injuries Tintnialli page 322


下面是網路上關於指甲修補的技術圖片.












































在uptodate裡面提到. 使用稀釋的優碘清洗指甲. 在中間挖出 3-4 mm 的洞. 可用組織膠將指甲黏回甲床. 但要精確放入 eponychium.
Protect the repaired nail bed by splinting with the original nail, if possible:

•Gently clean the nail in a dilute solution of povidone iodine and normal saline.

•Place a large hole, 3 to 4 mm in diameter, in the center of the nail using a sterile needle, scalpel, or electrocautery to allow drainage.

•Replace the nail beneath the proximal fold (picture 4). The least invasive technique to secure the nail in position is via a tissue adhesive (eg, Dermabond, Surgiseal, Histoacryl Blue, or Periacryl) [13,15]. The nail should be positioned in precise anatomic position by ensuring that the proximal aspect of the nail is underneath the eponychium in order to protect the germinal matrix. Place two to three drops of tissue glue in the areas of the nail folds and allow the stream of adhesive to seal the nail to the skin. Alternatively, the nail plate may be sutured in place through the lateral skin folds with two 4.0 chromic sutures.

Although silicone splints are available, a retrospective analysis of complications after nail splinting with native nail versus silicone nail revealed significantly fewer nail deformities when the native nail was replaced compared with splinting with a silicone product [16].

•If the original nail cannot be used, place a nonadherent splint consisting of a single thickness of nonadherent sterile gauze (eg, Telfa gauze), 0.20 inch reinforced silicon sheeting, or sterile foil from the suture packet in the proximal fold and suture in place through the lateral skin folds using absorbable 4-0 suture or use skin glue (picture 5). There are no comparative studies regarding which of these splinting material results in the best clinical outcomes.

Fingertip and Nailbed Injuries Hand Surgery 1st Edition © 2004 Lippincott Williams & Wilkins Fingertip and Nailbed Injuries (Adam B. Shafritz 手外科醫師 Edward P. Hayes)

A subungual hematoma is the result of some degree of trauma to the nailbed (7). In the event of nailbed injury, primary healing after accurate approximation of the nail matrix is essential for regrowth of a normal-appearing nail (2). Gaps heal by granulation tissue formation, leading to scar and nail deformity or nonadherence. The nail fold, composed of the dorsal roof and the ventral floor, must be maintained by some sort of stent to prevent adherence of the two surfaces by scar tissue. The replaced nail functions best for this purpose. The consequence of nail fold adherence is a split nail or a painful and inflamed nail as the nail cuts through the adhesions.

Distal phalanx fractures usually disrupt the nailbed but may leave the nail plate unaffected (7). A distal phalangeal fracture with palmar angulation combined with a transverse nailbed laceration can deliver the proximal nail plate out of the dorsal nail fold. The Seymour fracture involves a similar nailbed injury occurring with an apex dorsal-angulated Salter-Harris I injury of the distal phalanx (8).

NAILBED INJURIES: NONOPERATIVE TREATMENT
Options and Indications
Nailbed injuries present with, at the very least, a subungual hematoma. In the event of an intact nail plate and nail margin, the pressure of the hematoma can cause marked throbbing pain. According to Zook and Brown, a subungual hematoma involving at least 25% to 50% of the nail surface area may represent a significant nailbed injury and warrants removal of the nail plate for nailbed inspection and repair (13). A lesser procedure, trephination 甲床穿孔術 of a fingernail and evacuation of the subungual hematoma, can be performed safely with cautery, a heated paper clip, an 18-gauge needle, or an 11-scapel blade.
The traditional teaching mandating nailbed exploration and repair has been challenged in a recent prospective study of childhood fingernail crush injuries randomized into operative and nonoperative treatment groups (14). All patients had a subungual hematoma with an intact nail plate and paronychium and no previous nail abnormality. There was no notable difference in outcome between children treated with nailbed repair and those treated conservatively regardless of hematoma size, presence of fracture, injury mechanism, or age. Monetary charges were substantially higher for the operative group. The authors concluded that nail removal and nailbed exploration is not indicated or justified for children with subungual hematoma, an intact nail, and nail margin.
Authors’ Preferred Treatment and Techniques 如果甲床下的瘀血面積超過 50%. 要考慮合併甲床損傷. 建議移除指甲. 檢查修補甲床.
In the case of a small subungual hematoma (less than 50% of the nail surface area), the authors generally reserve trephination for those patients with moderate to severe pain despite analgesics. For a painful subungual hematoma with an intact nail plate and paronychial tissues and no fracture, trephination using an 11-scapel blade or a 16- to 20-gauge hypodermic needle in a twirling fashion is performed to perforate the nail plate over the hematoma. If more than 50% of the nail is undermined by the hematoma and if a high-energy injury mechanism is involved, consider nail plate removal and nailbed exploration and repair. Often, a stellate and displaced nailbed injury is found under these circumstances.

NAILBED INJURIES: SURGICAL MANAGEMENT 手術時機
Options and Indications 指頭骨折移位. 甲床近端斷裂. 甲床翻出.
Clear indications for surgical intervention are a nailbed injury with associated displaced distal phalangeal fracture, disruption of the dorsal nail fold or other paronychial tissues, or a disrupted or avulsed nail plate.
Results, Review of the Literature, and Factors Affecting Outcome
The standard principles of establishing a sterile surgical field as well as antibiotic and tetanus prophylaxis apply in surgical management of nailbed injuries. For adults, meta-carpal block anesthesia is usually adequate. General anesthesia may be required for children. A blood-free field maintained by a digital tourniquet and the use of loupe magnification are essential for good results (1). Lacerations are repaired after removal of the nail plate. The nail plate is usually quite adherent to the sterile matrix. A careful, atraumatic technique helps avoid iatrogenic injury to the nailbed (7). The use of tenotomy scissors has been described for this process, but a Freer elevator or a small hemostat is a gentler and less risky instrument to introduce under the nail plate for exposure of the sterile matrix.
Aggressive irrigation and débridement are to be avoided; all nailbed tissue should be preserved (1). Reduction and internal fixation of a displaced or unstable distal phalanx fracture should proceed first. If fracture fragments are large enough, Kirschner wire fixation can be used (Fig. 2). Usually, a .028- or .035-in. wire will suffice. If possible, avoid transfixing the DIP joint. Care must be taken to avoid iatrogenic nailbed injury by too dorsal placement of the wire. A nondisplaced or highly comminuted fracture may be adequately stabilized with a combination of soft tissue repair and replacement of the nail plate. Using the replaced nail plate as a native splint after nailbed repair is also effective in restoring stability to open epiphyseal fractures of the distal phalanx in children.

DORSAL TENSION BAND SUTURE 手術三周之後移除縫線.










Supplemental fixation can also be achieved with a dorsal tension band suture placed after nailbed repair and replacement of the nail plate (15). The nonabsorbable monofilament suture is placed proximally in a transverse manner superficial to the germinal matrix through the dorsal nail fold and distally in the opposite transverse direction through the fingertip pulp just distal to the nail. The suture forms a figure-of-eight loop crossing dorsally over the replaced nail. The suture is removed at approximately 3 weeks postoperatively.

如果可以. 將甲床種回去. 可當成骨折的固定器. 保護軟組織. 提供新指甲生長的模板. 避免甲床與 dorsal nail fold 沾黏.

FIGURE 2. Repair of the fingertip and nailbed. The nail plate is gently removed. Unstable fractures of the distal phalanx are reduced and held with a Kirschner wire (K-wire). The nailbed is repaired using fine resorbable suture. Any associated injury to the paronychium and eponychium is also repaired. Pulp injuries are addressed. A drainage hole is placed into the nail plate before reinsertion and fixation with a suture. (Redrawn from Van Beek AL, Kassan MA, Adson MH, et al. Management of acute fingernail injuries. Hand Clin 1990;6:23–38, with permission.)
The best way to achieve a smooth nailbed healed by primary intention is to accurately approximate the edges of lacerations using fine suture (6-0 or 7-0 chromic gut) under magnification (1,2). If the laceration involves the germinal matrix, exposure is obtained by incisions through the dorsal nail fold at perpendicular angles from the eponychial border. These nail fold incisions are also helpful when the proximal nail plate is displaced out of the dorsal nail fold, usually seen with a distal phalangeal fracture or epiphyseal injury and a transverse nailbed laceration. Paronychial lacerations, usually involving the lateral nail folds, should be repaired using 5-0 nylon. Associated injuries of the paronychium and the dorsal nail fold must be meticulously repaired, as they serve as “runners” guiding new nail growth along the appropriate path. If available, the cleaned nail should be placed over the bed and into the nail fold. This additionally splints fractures, protects soft tissue repairs, provides a template for new nail growth, and prevents adhesion formation between the nailbed and the dorsal nail fold.

如果沒有指甲可以種回去. 可使用矽膠片. 或使用縫線包裝的塑膠材料剪成指甲形狀.
Adherent dressings on the raw nailbed are difficult and painful to remove (16). If the nail plate is not available, a silicone sheet or a carefully contoured piece of foil from suture packaging serves the purpose. Replacement of a fractured nail plate repaired with tissue adhesives has also been described (9).
As expected, crush and avulsion injuries, especially those associated with phalangeal fractures, have a worse prognosis than isolated simple and stellate lacerations. Associated injuries to the paronychium and the fingertip pulp also portend a poorer outcome (1). A proximally detached and avulsed germinal matrix is replaced deep to the dorsal nail fold and secured with horizontal mattress sutures tied over the dorsal skin of the nail fold (17). Completely avulsed pieces of sterile or germinal matrix can be sutured into place in the defect directly on the cortex of the distal phalanx. All retrievable pieces of nailbed should be used as grafts, and this includes grafts from unsalvageable digits in severe trauma. In cases of loss of matrix tissue, the nail plate should be inspected for pieces of adherent nailbed. The avulsed tissue can be carefully removed with a scalpel to serve as a graft for repair. When a small fragment of nail plate is adhered to a similar-sized avulsed piece of nailbed, the nail plate along the margins can be trimmed, leaving exposed nailbed, and the composite graft can be sutured to the defect. Shepard reported 85% good results with these techniques of repair of nailbed avulsions (17). The repairs of germinal matrix avulsions were associated with more nail deformity than those of the sterile matrix.
When tissue is not available for repair of defects of the sterile matrix, split thickness nail grafts can be raised from a donor bed (18). The donor site may be from an uninjured portion of the sterile matrix on the affected digit (rarely possible), from an unsalvageable amputated digit, or from the great toe. To avoid a donor site deformity, the graft must be very thin, on the order of seven to ten thousandths of an inch. Expecting some degree of contracture, the graft should be 1 to 2 mm larger than the defect. The longitudinal axis of the graft should be parallel to the defect. The replaced nail plate and an overlying firm dressing are applied. Split-thickness sterile matrix grafts represent a substantial improvement over previous treatments for nailbed tissue loss, including allowing healing with granulation tissue, skin grafts, dermal grafts, reversed dermal grafts, and xenografts.
Loss of the nail plate, nailbed, and periosteum over the exposed distal phalanx can be reconstructed by a split-thickness nailbed graft placed directly on granulating decorticated bone (19). Loss of germinal matrix, provided the defect is not too extensive, can be treated by local rotational or bipedicle flaps (13,17). Local rotation of the full-thickness germinal and sterile matrices on proximally based flaps have been used with success to cover devitalized bone graft to the distal phalanx, a tribute to the robust vascularity of the proximal nailbed. Although the vascular germinal matrix tissues can withstand undermining, they do not advance very far. Larger defects involving greater than one-third of the germinal matrix can be treated with split-thickness germinal matrix grafts from an adjacent area or from the great toe. Split- or full-thickness germinal matrix grafts are not as successful as sterile matrix grafts; both the donor and recipient sites often have some degree of residual deformity. Finally, whole, free, vascularized toenail transfers for reconstruction of congenital and traumatic nailbed defects have been described and, in small series, achieve excellent cosmetic results while maintaining normal hand function (20).

When confronted with loss of dorsal nail fold tissue, the surgeon must remember that the dorsal nail fold has specialized epithelium in direct contact with the nail (1,21). This specialized matrix tissue has some contribution to nail formation and also imparts the shine seen on the nail surface. The contribution of the dorsal nail fold to nail production can sometimes be seen after fingertip amputations when the retained dorsal fold tissues produce painful nail spicules. Reconstruction of tissue loss to the dorsal nail fold is best accomplished with a dorsal rotational skin flap or a reversed cross-finger flap (22). Reconstruction of the specialized matrix of the dorsal nail fold has been successfully achieved using a layer of split-thickness sterile matrix graft sutured to the undersurface of a local rotational skin graft (17).
Authors’ Preferred Treatment, Techniques, Surgical Pearls, and Pitfalls
The described principles of nailbed injury care are commonly used in the authors’ practices. Careful attention to detail in the treatment of these common injuries is suggested. The majority of these procedures can be performed under digital block anesthesia in a well-equipped procedure room. To decrease the risk of subungual contamination and subsequent infections, including osteomyelitis, the affected digit should have a standard surgical scrub before nail removal or trephination. Twenty-four hours of oral antibiotics is generally recommended, but the benefit of prophylactic antibiotics is not proven under these circumstances.
A frequently seen pitfall is iatrogenic injury to the remaining nailbed by too aggressive and impatient removal of the nail plate. After the nailbed repair, we place a small drainage hole in the replaced nail plate to facilitate drainage of any hematoma. The nail plate is sutured proximally deep to the dorsal nail fold and distally to the fingertip pulp with horizontal mattress nylon sutures. The dorsal tension band suture technique is an effective and minimally invasive means of fixation of associated distal phalangeal fractures. Kirschner wire fixation for very unstable fractures is used. Unless there is special concern about tissue viability or infection, the operative dressing is generally left in place for 7 to 10 days. Earlier dressing removal is unnecessarily painful and risks avulsion of the replaced nail plate. Long-term follow-up, on the order of 1 year, is needed to adequately assess and learn from the results of treatment of these injuries. The surgical repair is best reflected in the appearance of the resulting nail plate.
Postoperative Rehabilitation
Scar reduction techniques and fingertip desensitization begin roughly 2 weeks from injury, once the wounds have stabilized (7). The replaced nail plate or other stent under the dorsal nail fold will be pushed out by the new nail at 2 to 3 weeks. In the event of no fracture or only a minimal tuft fracture, early range of motion is preferable. Generally, 3 to 4 weeks of protected immobilization of the DIP joint is allowed if there is an unstable distal phalanx fracture. Kirschner wire removal occurs at 4 weeks. A custom fingertip protector can be fashioned to allow early return to work and activities of daily living.
Complications: Etiology, Prevention, Incidence, and Classification
Iatrogenic nailbed deformities have resulted from too vigorous nail plate trephination and removal (9,23). Anatomic repair of a nailbed injury usually results in minimal scar and no significant disruption between the continuum of cells from the nailbed into the nail plate. A wide scar inhibits the cellular continuity over the scarred area and frequently along the entire nailbed distal to the scar. Gaps heal by granulation formation, leading to scar and nail deformity or nonadherence. Distal nonadherence results in loss of the protective hyponychium, leading to the accumulation of foreign material under the nail and predisposing to infection. Proximal nonadherence is even more troublesome, leading to an unstable nail prone to being torn loose. The use of slowly absorbing and large sutures for nailbed repair may cause nail ridging and nonadherence.
Associated distal phalangeal fractures require accurate reduction, as poor alignment of the dorsal cortex leads to nailbed irregularities. Care must also be taken with Kirschner wire placement; superficial wire placement and nailbed injury can lead to longitudinal nail ridging. In the event of distal phalangeal bone loss, care must be taken to ensure adequate distal bone support for the nailbed; otherwise, a hooked or beaked nail can result.
Clinical History, Physical Examination, Office Tests, and Imaging Studies
The distal phalanx must be imaged when faced with nail deformities (24). Nailbed deformities are most often the sequelae of trauma. Malalignment of a distal phalanx fracture or a bone spur commonly leads to nonadherence and other nail deformities. Occasionally, axial cuts of a CT scan through the distal phalanx are beneficial.

Operative Management
Excessive nail matrix scar is the cause of nonadherence. The treatment is excision of the scar (23,24). Closing the defect should not be done under tension and usually necessitates a split-thickness sterile or germinal matrix graft. Malreduced distal phalanx fractures and exostoses commonly lead to nonadherence or ridging of the nail plate. The underlying bone abnormality must be assessed and corrected (Fig. 3).
A longitudinal scar in the germinal or sterile matrices, or both, can cause a split nail plate. The treatment is similar to above with complete excision of the intervening scar (often requiring a microscope) and split-thickness grafting of sterile matrix. More than minimal loss of the germinal matrix requires a local rotational flap, or, more commonly, a germinal matrix graft from the toe. A sterile matrix graft, even if full thickness, will not suffice for a germinal matrix defect.
Adhesions between the dorsal nail fold and the germinal matrix can produce split nails. Reconstructions for loss of tissue or adhesions of the dorsal nail fold must take into account the unique epithelium lining the undersurface of the dorsal nail fold. This tissue assists in nail formation and imparts shine to the nail. Successful reconstructions of split nails have been reported using split-thickness sterile matrix grafts to the undersurface of the dorsal nail fold, coupled with careful postoperative stenting of this space to prevent adhesions.

FIGURE 3. Repair of a ridged and partially nonadherent nail. A: The sterile matrix is exposed. B,C: Scar tissue is excised. D: The distal phalanx is recontoured. E,F: The sterile matrix is repaired primarily and grafted if necessary. (Redrawn from Shepard GH. Nail grafts for reconstruction. Hand Clin 1990;6:79–103, with permission.)
A crooked nail plate curves to one side during longitudinal growth (24). This is caused by sterile matrix scar contracture on one side. After scar excision, the defect requires a full-thickness nail matrix graft. The use of partial-thickness grafts or allowing healing by secondary intention results in excessive contracture and recurrence of the crooked nail deformity.
The hooked nail can result from congenital deficiency of the fingertip, but it most often is a posttraumatic deformity. The usual cause is insufficient bone support of the sterile matrix. A common error in the treatment of fingertip amputations with an associated nailbed injury is to pull the nailbed tissue distally over the exposed distal phalanx. Prevention is the key. Because the shape of the nail plate follows the contour of the nailbed, the nail plate curves palmarly over the fingertip pulp. Healing by secondary intention can allow for significant contracture of the dorsal soft tissues and draw the nailbed distally. The hooked nail deformity can be avoided by ensuring adequate distal bone support of the nailbed and by avoiding tension in re-approximating the dorsal and palmar soft tissues.
The distal edge of the sterile matrix should be at least 2 mm proximal to the distal extent of the distal phalanx bone stock. Two steps may be necessary to address this problem. First is correction of the mismatch between the distal phalanx and the nailbed. Options include shortening the nailbed, releasing the nailbed and allowing it to retract dorsally, and lengthening or osteotomy of the distal phalanx. After correction of the nailbed-bone relationship, soft tissue coverage for the fingertip is needed. Options include advancement of local tissues, full-thickness skin grafts, and regional or distant flaps (25).

Fingertip injuries can include a wide variety of injuries and can be successfully managed by a spectrum of options from simple nonoperative treatments to rather complicated reconstruction techniques. As summarized by Ma et al. (26), regardless of the treatment option chosen and the experience and/or level of training of the treating surgeon, the results of many treatments yield similar good results. This portion of the chapter focuses primarily on both nonoperative treatments of fingertip injuries with or without associated nailbed injuries and simple operative procedures (flaps) on the fingertip.
For fingertip amputations and injuries, a wide variety of classification schemes exist (27,28,29,30,31,32 and 33).

These classification systems are based on amputation level, obliquity, nailbed involvement, and/or bone exposure. A practical simplification divides these injuries into two main categories of amputations and fingertip injuries: those that include skin and/or pulp loss but do not involve exposed bone, and those that involve exposed bone. This simple classification system helps to guide the surgeon’s treatment options and decisions, especially if replantation is not considered to be a viable option.

Nonoperative Treatment: Results and Outcome, Review of the Literature, and Factors Affecting Outcome
Options and Indications
Numerous methods have been devised and reported over the years for nonoperative treatment of pulp and skin loss on the tip of the digit. Usually, nonoperative treatment is recommended for injuries that do not involve exposed bone. The simplest method of nonoperative therapy involves simple mechanical débridement followed by the application of an antibiotic ointment to the fingertip, a nonadherent sterile dressing, tube gauze, and fingertip protector cap. Examples of these nonadherent dressings include OpSite (Smith and Nephew), Xeroform (Sherwood Medical), Adaptic (Johnson and Johnson Medical), Vaseline gauze (Sherwood Medical), and Owens (Davis and Geck).
The results of simple open treatment have been reported with the use of an OpSite dressing (34,35). Mennen and Wiese reported on 200 fingertip injuries treated simply with an OpSite over the injured fingertip after local irrigation and débridement (34). The theory behind the treatment protocol is that a semi-occlusive dressing provides a temporary “skin” that would allow for healing of the underlying soft tissues in an optimal environment, thereby promoting earlier granulation tissue formation and epithelialization of the wound. In their study, the authors found that the use of a simple weekly dressing change of an OpSite resulted in near normal pulp shape and useful epithelium of an injured fingertip within a period of 20 to 30 days. They thought that the dressing should not be changed any more frequently than once per week, as this would slow healing. This method was used regardless of whether bone of the distal phalanx was exposed. They had no complications requiring surgery, and no patients developed a significant hook nail deformity. Patients recovered and regenerated a nearly normal pulp with excellent tactile sensation. In a similar study, Williamson et al. reported favorable results using similar materials on 40 patients (36).
Using a different technique, Fox et al. reported on 18 adults treated nonoperatively with a simple wound cleansing followed by coverage with an occlusive dressing made from sterile aluminum foil and gauze (37). Dressing changes were performed on the third, fifth, and seventh day, and then weekly until the wound healed. They reported that although at 2 weeks into the treatment the wound did not appear aesthetically pleasing, healing of the amputated fingertip occurred within 4 weeks, and the resultant fingertip had excellent sensory perception. Normal digital range of motion was noted, and acceptable cosmetic appearance was the rule. They thought that this outcome was satisfactory to all and resulted in less than 10 days lost from work.
A study by Buckley et al. reviewed the results of patients treated conservatively with silver sulfadiazine dressing changes performed on 21 digits, six of which had exposed bone (38). An occlusive dressing of Vaseline gauze with silver sulfadiazine covered by a finger portion of a disposable rubber glove was fashioned. The dressing was changed every other day during the first week and then on an as-needed basis until healed (range, 19 to 90 days). The cases were reviewed at an interval of 2 to 8 years after injury. All of the patients were satisfied with the treatment and the cosmetic appearance. Complications included minor nail abnormalities in 29% of patients, scar tenderness in 19%, and variable degrees of cold intolerance in 38%. Two-point discrimination was normal in all. All preferred the results obtained versus a revision amputation, digital shortening, and primary closure.
Ipsen et al. reported a prospective investigation of 81 consecutive fingertip injuries in which conservative treatment was used (39). The fingertip injuries were defined as greater than or equal to 1 cm × 2 cm in the distal phalanx without any joint or tendon injuries. All of the wounds were cleansed and covered with simple Vaseline gauze. If bone was exposed, 2 to 3 mm of bone was removed with a rongeur, and the wound was dressed in the same manner. Dressings were changed to fresh Vaseline gauze via soaks on day 5 and then weekly until healed. The average healing time was 25 days, with complications of scar tenderness in 26% of patients, cold intolerance in 36%, and nail deformities in 58%. In a similar study, Lamon et al. studied 25 fingertip amputations treated by débridement and application of bacitracin ointment and simple gauze dressings (40). The dressings were changed after 48 hours and then a three-times daily program of warm soaks in mild soapy water for 10 minutes followed by application of bacitracin and gauze dressing was instituted. This regimen was continued until the wound healed. Exposed bone was present in six cases. The average time to healing was 29 days. Those patients who were able to return to work (those who could keep their fingers clean and dry) were able to do so after 24 hours. Three patients had minimal sensory changes, there were no infections, and there were no significant complications reported with the use of this technique.
The use of Mepitel silicone net dressing (SCA Molnlycke Ltd, Bedfordshire, UK) was recently reported by O’Donovan et al. (41). They compared the silicone dressing to traditional
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dressings used on fingertip injuries in children ages 6 months to 11 years. During the first 3 weeks of dressing changes, the Mepitel net prevented adherence of the wound to the outer dressing and therefore significantly reduced the pain and anxiety suffered by the children associated with wound care. There was no difference in time of wound healing associated with this method when compared to other methods.
The use of chitin as a biologic dressing for fingertip injury has been reported (42,43). Hyphecan artificial skin membrane (Hainan Kangda Marine Biomedical Corp., China) is an occlusive fingertip dressing made of a chitin derivative (1-4,2-acetamide-deoxy-beta-D-glucan) that is extracted from shellfish exoskeleton. It is nonantigenic and thus does not cause systemic allergic reactions. It is semipermeable and maintains a sterile environment without wound dehydration. The protocol for its use requires a simple local irrigation and débridement and application of the Hyphecan cap and sterile gauze over the cap. The cap is not changed. It is slowly cut away as it dries and separates from the wound as it heals. Excellent results have been reported in 276 fingertip injuries treated in such a manner (42,43). No significant complications were reported, and all patients were satisfied with form and function of the injured finger. No revision surgery was needed in any case.
Finally, Ma et al. (26) reported on the treatment of fingertip injuries using a simple dressing, split-thickness skin grafting, full-thickness skin grafting, V-Y advancement flaps (both Kutler and Atasoy), revision amputation and primary closure, and cross-finger flap. In their series of 200 randomized patients, they found little difference in the ultimate results among any of the methods used.
Authors’ Preferred Method of Treatment
If nonoperative treatment is going to be accepted by the physician and patient, these injuries are easily treated and serially followed until healing is assured. It is probably not appropriate to elect nonoperative treatment if a skin defect larger than 1 cm × 2 cm is present, and/or if there is exposed bone present. The patient is evaluated in the emergency department or office, and a digital block is used to allow for adequate débridement of the fingertip injury in a painless fashion. After adequate débridement is performed, Bactroban ointment (2% Mupirocin ointment, SmithKline Beecham Pharmaceuticals, Philadelphia, PA) is applied to the wound and covered by Xeroform nonadherent dressing. The finger is then covered with gauze, and a simple fingertip tube–type dressing is applied. A metal cap fingertip protector is placed over the dressing to prevent the patient from inadvertently injuring the finger. This dressing is kept clean and dry until the patient is reevaluated. Mild narcotics and oral antibiotics (cephalexin or clindamycin if patient is allergic to penicillin) are usually prescribed for a short course but have not been shown to affect outcome.
A wound check is performed at 2 or 3 days. The old occlusive dressing can be soaked off in a sterile saline solution. The fingertip is then reevaluated for further demarcation of injury and necrosis. Further débridement may be performed in the office. A repeat application of a similar dressing is then placed, and the patient is examined at weekly intervals with weekly dressing changes. As the wound gradually begins to granulate, the patient can perform dressing changes as necessary at home, unsupervised.
If an adequate débridement cannot be obtained from a single time in the emergency department or office (e.g., if there is grease or other organic matter embedded in the pulp), the patient is referred to the hand therapy unit for sterile whirlpool débridement of the fingertip. This treatment is begun after the patient has been seen for the first follow-up examination and is performed on a daily basis. After each treatment session, the fingertip is dressed with antibiotic ointment, nonadherent dressing, and clean gauze. The patient is reassessed twice weekly until there is evidence of granulation without any evidence of infection. Once this is accomplished, the patient can then be monitored on a weekly basis, and the patient can be instructed on home dressing changes. Depending on size of the involved skin loss and pulp loss, the patient may need to be followed conservatively over 4 to 6 weeks. Many patients need reassurance that the wound will heal and that good results are the rule (Fig. 4).
Surgical Management: Results and Outcome, Review of the Literature, and Factors Affecting Outcome
Options and Indications
If nonoperative therapy is not acceptable to the patient and/or if there is exposed bone with soft tissue and skin loss as well as nailbed injury, then surgical management is considered. Six commonly used methods of acute fingertip reconstruction are reviewed. Four of these procedures can be performed in the emergency department or a well-equipped procedure room. These include the “cap” procedure or composite grafting, the Kutler repair, the Atasoy V-Y advancement flap, and revision amputation and primary closure. The cross-finger flap and thenar flap and its variations are also discussed; however, it is recommended that this operative procedure be performed formally in the operating room. Finally, some special situations and alternative local flaps are reviewed.
“Cap” Technique (Composite Grafting)
The “cap” technique is nonmicrosurgical reattachment of fingertip amputations (6). This method of treatment is effectively used in children and adults who have amputated
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their fingertip through the mid-level or distal to the nailbed, either by a guillotine-type amputation or by avulsion. The technique can be performed in the setting of a dirty wound that would not be suitable for formal replantation. The procedure requires the presence of the amputated part for reattachment. For young children, it is recommended to proceed to the operating room so that adequate anesthesia and sedation can be achieved. It is important to explain to family members and the patient (if appropriate age) that this procedure is not a true replantation, rather that it is a way of reattaching the amputated part to form a “biologic dressing” or scab. This procedure allows for granulation tissue to form underneath the amputated part as the body naturally heals the fingertip over time. The patient and/or family members must be informed that the replanted part will undergo necrosis and desiccation. Eventually, over the course of 4 to 6 weeks, it will form a scab and fall off, leaving behind a well-healed fingertip. This procedure is quite effective at restoring, overall, a normal looking fingertip. However, this fingertip will not be identical to its uninjured counterparts.

FIGURE 4. A–D: Nonoperative treatment of fingertip injuries. A,B: The photographs demonstrate full-thickness skin and pulp loss to the fingertips as well as exposed bone of the distal phalanx of the thumb, resulting from a blast injury from fireworks. Note the damage to the paronychium and nail fold. Simple dressing changes were performed for 2 months. The results at 2 months are shown in panels C andD.
Operative Procedure
Composite grafting may be performed in the emergency department or in the operating room with digital anesthesia and the use of a finger tourniquet. After adequate débridement of both the injured finger and the recovered fingertip, the nail plate is removed from the amputated part as well as from the digit. If bone is present in the amputated part, it is cleared using a rongeur or a knife. Excess fat and subcutaneous tissue are removed from the
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amputated part. The skin edges, subcutaneous tissue, and bony end of the finger are débrided. The fingertip and amputated portion are simply sutured using a resorbable stitch such as 6-0 chromic gut (Fig. 5). The nailbed is repaired to itself as well, if possible. Once the portion of the digit has been reattached, sterile dressings are applied after release of the finger tourniquet. Reevaluation occurs at 5 to 7 days.

FIGURE 5. A–D: Composite grafting (“cap” technique). A 2-year-old boy sustained an amputation through the mid-nailbed (A). The wound was grossly contaminated with grease on presentation. After débridement, the fingertip was reattached (B). It underwent necrosis and desiccation as expected (C) and fell off 2 months later. His results at 5 months are shown (D).
The results of this technique were evaluated by Rose et al., and they reported on seven adults treated in this manner (6). They found that this procedure was effective at returning the fingertip to a near-normal appearance, that the mean two-point discrimination was 6.5 mm, and though the finger was shortened an average of 6 mm, it did give the illusion of a normal fingertip. There were no infections, and, overall, satisfactory results were the rule.
Atasoy Volar V-Y Advancement Flap
The Atasoy volar V-Y advancement flap has been attributed to Tranquilli-Leali (44) as described in 1935, but gained its commonly used eponym when Atasoy et al. published their results in 1970 (45). The flap may be used with transverse or dorsal oblique injuries to the fingertip involving both the nailbed and the pulp with exposed bone. It is less useful when a palmar oblique fingertip amputation is encountered. The technique is based on a V-Y full-thickness advancement of the digital pulp over the tip of the finger. It is important when considering this technique to remove any excess or redundant nailbed to avoid the hooked nail deformity. Atasoy et al. reported on their results in 1970 and found that 56 of 61 of patients had near-normal motion and sensibility in their fingertip (45). However, these findings were contradicted by Tupper and Miller when they reported decreased sensibility in 15 of 16 patients and that 50% of patients developed cold intolerance after the Atasoy V-Y flap was performed (46). Three patients had a mild hook nail deformity, and 2 of the 16 patients (12.5%) were dissatisfied with their final results.
Operative Procedure
The Atasoy volar V-Y advancement flap can be performed in the emergency department
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with a simple digital block and digital tourniquet. After surgical prep and drape, excess sterile matrix is removed 1 to 2 mm proximal to the bone of the distal phalanx. The bone may need to be shortened using a rongeur (Fig. 6). Next, a full-thickness skin flap of digital pulp is brought up, with care not to injure the flexor digitorum profundus attachment and the vascular supply to the flap. The procedure should be carried out with loupe magnification to ensure preservation of the small-caliber vessels supplying the flap during division of the fibrous connections securing the flap. Care must also be taken to avoid crossing the DIP flexion crease; otherwise, a contracture may ensue. The palmar flap is mobilized distally and dorsally, and a nailbed repair directly to the distal edge of the flap is performed using a 6-0 chromic gut suture. The medial and lateral portions of this flap are then sutured to the remaining digital pulp using either an absorbable or nonabsorbable suture (a 4-0 nylon or Prolene stitch is sufficient). Finally, the more proximal portion of the V is closed on itself using this same suture.
Kutler Lateral V-Y Flaps
William Kutler described his procedure of creating two lateral V-Y flaps to close fingertip amputations in 1947 (47). It remains useful in treating transverse amputations of the distal phalanx through the level of the nail and nailbed. Like the Atasoy flap, it can be performed under digital anesthesia in the emergency department. Two simple lateral V-Y advancement flaps are created to meet in the midline of the digit. The procedure is thus suitable for dorsal oblique and transverse amputations, but is less applicable to palmar oblique amputations. This procedure is described below and shown in Figure 7.

FIGURE 6. The Atasoy volar V-Y advancement flap. A: The fingertip is débrided, and bone is shortened if necessary. B: A full-thickness triangular palmar flap is developed and advanced to the sterile matrix. The skin is then closed as illustrated (C). [Redrawn from Atasoy E, Ioakimidis E, Kasdan M, et al. Reconstruction of the amputated finger tip with a triangular volar flap. J Bone Joint Surg 1970;52(A):921–926, with permission.]

FIGURE 7. The Kutler lateral V-Y advancement flaps. The fingertip is débrided and bone is shortened if necessary. Two lateral full-thickness flaps are developed and advanced as shown. [Redrawn from Shepard GH. The use of lateral V-Y advancement flaps for fingertip reconstruction. J Hand Surg

輕度至中度嚴重的灰指甲-治療

2023-08-08 12:00 中午
健保給付規定: 10.6.4. Terbinafine ( 如 Lamisil tab ):(85/1/1、91/4/1、98/8/1)限 1.手指甲癬及足趾甲癬病例使用, 每日 250 mg,手指甲癬限用 42 顆,需於 8 週內使用完畢。足趾 甲癬限用 84 顆,需於 16 週內使 用完畢。治療結束日起算,各在 6 及 12 個月內不得重複使用本品或 其他同類口服藥品。(98/8/1) 2.其他頑固性體癬及股癬病例使 用,每日一次,最長使用 2 週, 治療期間不得併用其他同類藥 品。 3.頭癬病例使用,每日一次,最長使 用 4 週,若確需延長治療時間,須 於病歷詳細載明備查。(98/8/1)

輕度至中度定義: 影響 50% 以下指甲. 沒有侵犯至 Matrix 及 lunula
















治療選項包括一種口服藥物, 或數種外用藥物
口服藥物: Terbinafine 鹽酸特比萘芬 (商品是 Lamasil 療黴舒)
(下面 terbinafine 名稱都用療黴舒替代)

外用藥物:
efinaconazole (商品: 舒步利安外用液10% JUBLIA topical solution 10%)
amorolfine(商品Amocoat Nail Lacquer -5%;5mL/Bot雅舒安抗甲癬油劑)
tavaborole(商品 Kerydin® 5%外用溶液)
ciclopirox(商品 Brumixol Cream 1% 10gm膚爽乳膏)

口服抗黴菌藥物的療效與治療時間會優於外用藥(治癒率較高,治療時間較短)
不建議給予口服藥物的情況
1. 有治療禁忌患者
2. 因服用其他藥物, 有藥物交互作用疑慮
3. 感染部位較少(例如只有兩三個指甲受感染)

另外, 兒童通常建議用外用藥物, 使用 ciclopirox 反應較好

口服療黴舒是治療輕度至中度感染的第一線藥物, 使用方式與嚴重感染相同.
口服 Itraconazole (Sporanox Cap -100mg 適撲諾膠囊)可作為替代選擇. 當患者使用療黴舒治療無效. 或無法忍受口服療黴舒的副作用, 可以改用這個.
局部治療. 第一線選擇可使用 efinaconazole, amorolfine, tavaborole, and ciclopirox
目前並沒有高質量醫學研究證實哪一種外用藥物效果最好. 所以都可以選.
因為一般針對皮膚黴菌感染的外用藥物. 不一定能滲透指甲, 建議使用專門用於甲癬的商品.
下面是參考資料中對於各種外用藥物的描述. 


Efinaconazole (商品: 舒步利安外用液. 下面以中文商品名稱代替)


10%舒步利安是三唑類抗黴菌藥(具有五環結構)。兩篇第三期多中心隨機試驗, 分別收錄 870 及 785 名患者. 患者指甲受感染比例 20~50%, 沒有侵犯到 matrix 和 lunula, 
使用10%舒步利安, 每天一次治療 48 周, 治療結束四周 (開始治療後 52 周) 完全治癒率 18% 及 15%. 對照組的治癒率 3% 及 6%(有些人沒治療也自己好了? )
如果以 ≤5% 灰指甲做治療目標. 使用10%舒步利安達標的比例是 26% 及 23 %. 而使用安慰劑的達標比例是 7% 及 8% 

Amorolfine(商品Amocoat Nail Lacquer -5%;5mL/Bot雅舒安抗甲癬油劑)
在兩項劑量比較隨機試驗(同一藥物不同濃度)中,患者受感染的指甲<80%, 且 matrix, lunula 沒被感染, 每週一次使用雅舒安5% 指甲油治療6 個月,臨床治癒率 38% 和 46% 的患者 [ 13,14 ]。值得注意的是,在一項試驗中,臨床治愈被定義為完全清除或≤10%的指甲仍受影響[ 14 ],而在另一項試驗中沒有明確定義[ 13 ]。




參考資料: 下面內容來自uptodate. 每一段的中文是用google中文翻譯
Managemen of Mild to Moderate dermatophyte onychomycosis
的治療治療選擇— 輕至中度甲真菌病(例如,遠端外側甲下甲真菌病,累及指甲≤50%,不累及基質/月牙)的一線治療選擇包括口服特比萘芬和幾種外用藥物包括艾芬康唑、阿莫羅芬、他瓦硼羅環吡酮
Treatment selection — First-line treatment options for mild to moderate onychomycosis (eg, distal lateral subungual onychomycosis involving ≤50 percent involvement of the nail and sparing the matrix/lunula) include oral terbinafine and several topical agents including efinaconazole, amorolfine, tavaborole, and ciclopirox.
儘管口服抗真菌治療由於與局部治療相比具有更高的完全治愈率和更短的療程而被認為是甲真菌病的金標準治療,但臨床情況決定了口服治療是否是輕至中度甲真菌病最合適的一線治療。可能首選局部治療的情況示例包括:
Although oral antifungal therapy is considered the gold standard treatment for onychomycosis because of higher complete cure rates and shorter courses of treatment when compared with topical therapy, the clinical scenario determines whether oral therapy is the most appropriate first-line treatment for mild to moderate onychomycosis. Examples of scenarios in which topical therapy may be preferred include:
有全身抗真菌治療禁忌的患者
●有與全身抗真菌藥物發生藥物相互作用風險的患者
●傾向於避免全身治療的患者(尤其是涉及三個或更少指甲的患者)
●Patients with contraindications to systemic antifungal therapy
●Patients at risk for drug-drug interactions with systemic antifungal drugs
●Patients who prefer to avoid systemic treatment (especially with three or fewer nails involved)


兒童可能比成人更適合接受局部治療,因為兒童的指甲板更薄,指甲生長速度可能更快。一項小型隨機試驗表明,兒童對局部環吡酮產生反應的可能性更高[ 7 ]。(參見“環吡酮:藥物信息” )
Children may be more favorable candidates for topical therapy than adults because of a thinner nail plate and potentially faster nail growth rate. A small randomized trial suggested that the likelihood of response to topical ciclopirox is higher in children [7]. (See "Ciclopirox: Drug information".)


甲真菌病的治療費用差異很大,可能會影響治療選擇。2015年,在美國一療程的口服特比萘芬價格低至10美元。相比之下,艾夫康唑一個療程的費用超過 2000 美元[ 6 ]。
The cost of therapies for onychomycosis varies widely and may influence treatment selection. In 2015, a course of oral terbinafine could be obtained for as low as $10 in the United States. In contrast the cost of a course of treatment with efinaconazole was greater than $2000 [6].
口服特比萘芬 —特比萘芬是治療輕度至中度皮膚癬菌甲癬的一線口服藥物。治療方法與治療更嚴重疾病的特比萘芬相同。伊曲康唑是無法耐受特比萘芬或對特比萘芬無反應的患者的替代全身治療方法。(參見下文‘中度至重度皮膚癬菌性甲癬’ )
Oral terbinafine — Terbinafine is the first-line oral agent for mild to moderate dermatophyte onychomycosis. Treatment is given in the same manner as terbinafine therapy for more severe disease. Itraconazole is an alternative systemic treatment for patients who cannot tolerate terbinafine or fail to respond to terbinafine. (See 'Moderate to severe dermatophyte onychomycosis' below.)
局部治療 — 一線局部治療包括艾芬康唑、阿莫羅芬、他瓦硼羅環吡酮。由於缺乏高質量的頭對頭試驗,因此沒有足夠的數據來得出這些療法的比較療效的明確結論。
Topical therapy — First-line topical therapies include efinaconazole, amorolfine, tavaborole, and ciclopirox. High-quality, head-to-head trials are lacking, leaving insufficient data for definitive conclusions on the comparative efficacy of these therapies.
局部治療僅限於專門針對指甲疾病的藥物。由於指甲板的滲透性差,針對皮膚真菌感染開發的外用抗真菌藥物通常對甲真菌病效果不佳[ 8-10 ]。
Topical treatment is limited to agents specifically indicated for nail disease. Topical antifungal agents developed for cutaneous fungal infections generally are poorly effective for onychomycosis because of poor penetration of the nail plate [8-10].
艾芬康唑 —艾芬康唑是一種外用三唑類抗真菌藥。艾夫康唑治療甲真菌病的療效已在兩項III 期多中心隨機試驗(n = 870 和n = 785)中得到證實,其中皮膚癬菌或皮膚癬菌和念珠菌遠端外側甲下甲真菌病累及20% 至50% 的目標腳趾甲,且不影響基質和月牙以 3 比 1 的比例隨機接受 10% 艾夫康唑溶液或載體治療,每天一次,持續 48 週 [ 11]。治療結束後4 週,使用艾芬康唑治療的患者中分別有18% 和15% 的患者實現了完全治愈(目標指甲的臨床受累和真菌學治愈率為0%),而使用賦形劑治療的患者中只有3% 和6% 實現了完全治愈。對完全或幾乎完全治愈(目標趾甲臨床受累≤5%且真菌學治愈)的次要終點進行評估,艾夫康唑組的緩解率為26% 和23%,安慰劑組為7% 和8% 。
Efinaconazole — Efinaconazole is a topical triazole antifungal agent. The efficacy of efinaconazole for onychomycosis was demonstrated in two phase III multicenter randomized trials (n = 870 and n = 785) in which patients with dermatophytic or dermatophytic and candidal distal lateral subungual onychomycosis involving 20 to 50 percent of the target toenail and sparing the matrix and lunula were randomized in a 3 to 1 ratio to treatment with efinaconazole 10% solution or vehicle once daily for 48 weeks [11]. Four weeks after the end of treatment, complete cure (0 percent clinical involvement of the target nail and mycologic cure) was achieved by 18 and 15 percent of patients treated with efinaconazole compared with only 3 and 6 percent of patients treated with vehicle. Evaluation of the secondary endpoint of complete or almost complete cure (≤5 percent clinical involvement of the target toenail and mycologic cure) yielded response rates of 26 and 23 percent with efinaconazole and 7 and 8 percent for placebo.
艾立康唑將 10% 溶液直接塗在指甲上,每天一次,持續 48 週。在每個受影響的指甲表面滴一滴;對於大腳趾甲,應在腳趾甲末端再滴一滴。使用塗抹刷將溶液塗抹到腳趾甲床、鄰近的甲襞、甲下和指甲板的下表面。建議在治療期間避免修腳、塗指甲油或美甲產品。
Efinaconazole 10% solution is applied directly to the nails once daily for 48 weeks. One drop is applied to the surface of each affected nail; for the great toenail, an additional drop should be applied at the end of the toenail. The application brush is used to spread the solution to the toenail bed, adjacent nail folds, hyponychium, and undersurface of the nail plate. Avoidance of pedicures, nail polish, or cosmetic nail products is recommended during treatment.
艾芬康唑耐受性良好。腳趾甲向內生長和局部皮膚刺激或不適的情況很少發生。
Efinaconazole is well tolerated. Ingrown toenails and local skin irritation or discomfort occur infrequently.
阿莫羅芬 — 阿莫羅芬是一種外用抗真菌劑,具有對抗皮膚癬菌、酵母菌、二形性真菌以及多種絲狀和暗色真菌的活性[ 12]。該藥物在美國不可用。
Amorolfine — Amorolfine is a topical antifungal agent with activity against dermatophytes, yeasts, dimorphic fungi, and a variety of filamentous and dematiaceous fungi [12]. The drug is not available in the United States.
在兩項劑量比較隨機試驗中,每週一次使用阿莫羅芬5% 指甲油治療6 個月,治療累及不到80% 指甲表面且不累及指甲基質和月牙的甲真菌病,結果獲得了臨床治愈和真菌學治愈。 38% 和 46% 的患者 [ 13,14 ]。值得注意的是,在一項試驗中,臨床治愈被定義為完全清除或≤10%的指甲仍受影響[ 14 ],而在另一項試驗中沒有明確定義[ 13 ]。In two dose-comparison randomized trials, once-weekly application of amorolfine 5% nail lacquer for six months to onychomycosis involving less than 80 percent of the nail surface and lacking involvement of the nail matrix and lunula led to both clinical cure and mycologic cure in 38 and 46 percent of patients [13,14]. Of note, clinical cure was defined as complete clearance or ≤10 percent of nail remaining affected in one trial [14] and was not clearly defined in the other trial [13].
此外,有證據表明阿莫羅芬與口服抗真菌藥物聯合使用可能會提高治愈率[ 15 ]。在一項隨機、開放標籤試驗中比較特比萘芬(每天250 毫克,持續三個月)加阿莫羅芬(每週一次,持續12 個月)與單獨使用特比萘芬相比,接受聯合治療的患者更有可能實現臨床和真菌學治愈(59% 與45%)[16 ]。需要進一步的研究來確定哪些患者應該接受聯合治療。
In addition, there is evidence that amorolfine may increase cure rates when used in combination with oral antifungals [15]. In a randomized, open-label trial comparing terbinafine (250 mg per day for three months) plus amorolfine (once weekly for 12 months) versus terbinafine alone, patients who received combination therapy were more likely to achieve both clinical and mycologic cure (59 versus 45 percent) [16]. Further studies are necessary to determine which patients should be treated with combination therapy.
用一次性銼刀銼指甲表面並用酒精擦拭後,每週使用阿莫羅芬一次。指甲護理一般為六個月;腳趾甲的治療時間為 9 至 12 個月。局部皮膚刺激是一種不常見的副作用[ 14 ]。與需要每天使用的療法相比,較低的使用頻率(每週一次)可能有助於堅持治療[ 17]。
Amorolfine is applied once weekly after the surface of the nail is filed with a disposable file and wiped with alcohol. Fingernails are generally treated for six months; toenails are treated for 9 to 12 months. Local skin irritation is an uncommon side effect [14]. The lower frequency of application (once weekly) compared with therapies requiring daily application may facilitate adherence to therapy [17].
Tavaborole — Tavaborole 5% 溶液是一種 oxaborole 抗真菌劑。Tavaborole 在兩項多中心隨機試驗中進行了評估,其中共有 1194 名甲真菌病患者每天使用一次 5% Tavaborole 溶液或載體,持續 48 週。試驗中的患者有 20% 至 60% 的目標腳趾甲受累,並且缺乏皮膚癬菌瘤和月牙受累的臨床證據 [ 18]。在一項試驗中,接受 tavaborole 治療的患者中有 7% 在治療後實現了臨床治愈(沒有甲真菌病的臨床證據)和真菌學治愈,而媒介物組中只有 1% 的患者實現了治愈。在第二次試驗中,這些比率分別為 9% 和 2%。在兩項試驗中,完全或幾乎透明的指甲(遠端指甲營養不良或變色的比例<10%,甲剝離或甲下角化過度)加上真菌學陰性的比率,tavaborole 為15% 和18%,而媒介物為2% 和4%。
Tavaborole — Tavaborole 5% solution is an oxaborole antifungal agent. Tavaborole was evaluated in two multicenter randomized trials in which a total of 1194 patients with onychomycosis applied tavaborole 5% solution or vehicle once daily for 48 weeks. Patients in the trials had 20 to 60 percent involvement of the target toenail and lacked both clinical evidence of a dermatophytoma and involvement of the lunula [18]. In one trial, 7 percent of patients treated with tavaborole achieved both clinical cure (no clinical evidence of onychomycosis) and mycologic cure after treatment compared with only 1 percent of patients in the vehicle group. In the second trial, these rates were 9 and 2 percent, respectively. Rates of completely or almost clear nail (<10 percent of the distal nail dystrophic or discolored and minimal onycholysis or subungual hyperkeratosis) plus negative mycology in the two trials were 15 and 18 percent for tavaborole versus 2 and 4 percent for vehicle.
將 5% Tavaborole溶液塗抹在受感染腳趾甲的表面和遠端下方,每天一次,持續 48 週。潛在的副作用包括腳趾甲向內生長和局部皮膚剝落或刺激。
Tavaborole 5% solution is applied to the surface and under the distal tip of infected toenails once daily for 48 weeks. Potential side effects include ingrown toenail and local skin exfoliation or irritation.
環吡酮 —環吡酮是一種羥基吡啶酮衍生物,具有對抗皮膚癬菌、酵母菌和黴菌的活性[ 19 ]。兩項隨機對照試驗(n = 223 和n = 237)的綜合結果表明,在接受環吡酮8% 指甲治療的患者中,約7% 的患者完全消退,其中納入了遠端甲下甲真菌病(累及目標指甲的20% 至65%)的患者。每天使用漆,持續 48 週,而使用安慰劑的比例為 0.4% [ 20 ]。一項小型隨機試驗表明,兒童對局部環吡酮的反應可能更好。然而,還需要更多的研究來證實這一發現[ 7 ]。Ciclopirox — Ciclopirox is a hydroxypyridone derivative with activity against dermatophytes, yeasts, and molds [19]. Combined results from two randomized, controlled trials (n = 223 and n = 237) that included patients with distal subungual onychomycosis involving 20 to 65 percent of the target nail suggest that complete resolution occurs in approximately 7 percent of patients treated with ciclopirox 8% nail lacquer daily for 48 weeks compared with 0.4 percent using placebo [20]. A small randomized trial suggested that the likelihood of response to topical ciclopirox may be better in children; however, additional studies are necessary to confirm this finding [7].
隨機試驗也評估了環吡酮的療效與口服特比萘芬聯合使用[ 21,22 ]。沒有發現比單獨使用特比萘芬更大的臨床療效。研究報告稱聯合治療的真菌學治愈率更高;然而,這是在患者仍在接受局部環吡酮治療時進行評估的,這可能影響了檢測持續性真菌感染的能力。

Randomized trials have also evaluated the efficacy of ciclopirox in combination with oral terbinafine [21,22]. No greater clinical efficacy was found than with terbinafine alone. The studies reported higher rates of mycologic cure with combination therapy; however, this was assessed while the patients were still being treated with topical ciclopirox, which may have affected the ability to detect persistent fungal infection.
將 8%環吡酮指甲油每天一次塗抹在受影響的指甲、周圍 5 毫米的皮膚上,如果可能的話,還可塗抹在甲床、甲床和甲板下表面。每週一次用酒精將指甲擦拭乾淨,並定期去除指甲未附著的感染部分。治療持續至指甲清除或長達 48 週 [ 8 ]。
Ciclopirox 8% nail lacquer is applied once daily to the affected nail, 5 mm of surrounding skin, and to the nail bed, hyponychium, and undersurface of the nail plate if possible. The nail is wiped clean with alcohol once weekly, and the unattached infected part of the nail is removed periodically. Treatment is continued until nail clearance or up to 48 weeks [8].
環吡酮是一種耐受性良好的治療方法[ 23 ]。潛在的副作用包括暫時改變指甲和局部皮膚刺激。
Ciclopirox is a well-tolerated treatment [23]. Potential side effects include temporary nail changes and local skin irritation.






灰指甲-手術治療-拔指甲 Onychomycosis: Management

剛遇到灰指甲患者, 她說在醫院拔過五次腳趾甲. 之後擦藥治療.
之前沒用過這種方式. 所以查詢一下 uptodate. 
拔指甲的治癒率 33%~75% (吃口服藥的治癒率 59%). 好像也不怎麼高. 
不過這裡不能將口服與手術的直接相比
因為會手術的患者. 都是比較難治療的, 這些患者應該就是口服藥治療失敗的那一群. 
我覺得比較合理的看待方式應該是這樣(不知道有沒有錯). 
口服藥物治療
 59%治癒.
 41% 失敗
   口服藥物失敗患者. 採取手術方式之後, 約 15.19%~36.75% 痊癒. 
   口服 + 手術都無效的患者佔  14.25% ~ 35.81%

google中文翻譯
甲真菌病:治療
手術 — 手術切除指甲(指甲撕脫術)通常適用於僅靠藥物治療無法成功治療的患者[ 78 ]。局部或全身抗真菌治療通常在手術後開始。如果沒有隨後的全身或局部治療,復發很常見。(參見“指甲撕脫術和化學基質切除術”,關於‘指甲撕脫術’一節)

指甲撕脫術隨後抗真菌治療的療效數據有限。在一項隨機試驗中,比較了四種不同的外用酮康唑奧昔康唑的結果在40 名甲真菌病患者的指甲撕脫後的治療方案中,大約三分之一的患者未能完成治療,而在完成治療的患者中,真菌學治愈率在33% 至75% 之間[ 79 ]。患有完全營養不良型甲真菌病的患者從治療中獲益的可能性最小。

Onychomycosis: Management
Surgery — Surgical removal of the nail (nail avulsion) is typically reserved for patients who cannot be successfully treated with pharmacologic therapy alone [78]. Topical or systemic antifungal therapy is usually initiated after surgery. Recurrences are common in the absence of subsequent systemic or topical treatment. (See "Nail avulsion and chemical matricectomy", section on 'Nail avulsion'.)

Efficacy data on nail avulsion followed by antifungal therapy are limited. In a randomized trial comparing the results of four different topical ketoconazole or oxiconazole regimens after nail avulsion in 40 patients with onychomycosis, approximately one-third of patients failed to complete therapy and among patients who completed therapy, mycologic cure rates were between 33 and 75 percent [79]. Patients with total dystrophic onychomycosis were least likely to benefit from treatment.

2023年7月28日 星期五

戒菸服務用藥原則-111年6月修訂版

112-07-28 16:45 
戒菸治療第一次可開兩周藥物
之後每次最多開四周藥物(不能開成連續處方箋)
噴劑與其他藥物可共用. 但有條件限制
戒必適不能與其他藥物合併申報
戒必適衛教資訊-中國醫藥大學附設醫院




戒菸服務用藥原則 111-06 修訂版
1 「戒菸服務用藥原則」 111 年 6 月修正版
一、 藥品常規劑量(單一用藥時):
(一)Varenicline:1 毫克/次,每日 2 次。(戒必適CHAMPIX)
(二)Bupropion:150 毫克/次,每日 2 次。
(三)尼古丁貼片:每日 1 片。
(四)尼古丁咀嚼錠:依吸菸狀況而異,建議以 2-4 毫克劑型開始使用,每日 8-12 錠。
(五)尼古丁吸入劑:建議每日 6-12 藥匣。
(六)尼古丁口含錠:建議每日 9-15 錠。
(七)尼古丁噴霧劑:依吸菸狀況而異,每次 1-2 噴替代一支菸為原則,以一般平均每天吸 15 支 菸為例,建議一天 15-30 噴。(新增)

二、 劑量調整:
(一)處方 Varenicline 時,初次使用時,第 1 週用藥應遵循第 1-3 天 0.5 毫克/次、每日 1 次, 第 4-7 天 0.5 毫克/次、每日 2 次,如無異常則第 8 天起增加至 1 毫克/次、每日 2 次;後 續使用之起始劑量,由醫師依臨床狀況專業判斷。
(二)處方 Bupropion 時,初次使用時,之第 1-3 天應處方 150 毫克/次,每日 1 次,第 4 天以後 處方 150 毫克/次,每日 2 次;後續使用之起始劑量,由醫師依臨床狀況專業判斷。
(三)使用尼古丁藥物之個案,宜於吸菸量或臨床症狀改善後逐步遞減用藥劑量。若無法降低劑 量時,須於病歷或個案紀錄表說明原因
(例如:起始劑量過低、減少吸菸量後又增加吸菸量、菸癮或戒斷症狀加劇)。

三、 合併用藥規定:
(一)補助藥物治療以單一用藥為原則,「合併用藥」需符合下列任一條件,並於病歷或相關紀 錄文件中述明,始同意給付:
1. 曾經使用單一藥物治療失敗者。
2. 該療程中單一藥物治療達 2 週後,戒斷症狀仍顯著者。
3. 為重度吸菸者(平均每日吸菸量≧31 支)。
4. 經醫師或藥師評估,個案有生理、心理、社會之需求,經詳述需求及理由者。

(二)同意補助之「合併用藥」組合方式包括:
1. 合併尼古丁藥物:貼片+其他一種短效藥物。(合併用藥應視個案狀況減低合併用藥 之藥量)
2. Bupropion+任何一種尼古丁藥物。
(三)Varenicline 之合併用藥不予補助。

四、 開藥週數及間隔:
(一)初診個案開藥週數限制:第一療程個案初診時其處方以 1~2 週為原則,後續療程於初診日 期一年內不在此限(最多開 4 週)。另如有具體因素應載明於病歷或戒菸治療個案紀錄 表,則可視個案需求增加週數【最多開 4 週,適用情形:
1、預定出國或返回離島地區;
2、遠洋漁船船員出海作業或國際航線船舶船員出海服務;
3、疫情或天災等人力不可抗拒 因素。
以上情事應於病歷或戒菸治療個案紀錄表載明(包括事況說明及其發生之日期等), 並請個案簽名確認,以示負責】。
(二)複診時,使用戒菸輔助用藥,應依醫藥專業、個案成癮度及臨床症狀,並參照藥品仿單及 臨床戒菸服務指引,確信可以掌握個案戒菸情形,始開立超過 2 週之戒菸藥品數量,最多 開 4 週。

2023年7月27日 星期四

潛伏型結核感染治療- 3HP處方-副作用-肝毒性


2025-01-07
剛剛開立3HP處方. 目前是開一顆複方含兩種成分各 300mg. 每次吃900mg. 每周吃一次(我以前開的是兩顆藥物. 一種每周一次吃三顆. 一種每周一次吃6顆)
肝功能不良的需要調整劑量. 不能開一顆複方的藥物. 需兩種分開開立. 

潛伏結核感染專區







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2023-07-28 10:00am
台灣疾管署-使用「速克伏」治療潛伏結核感染臨床建議-2018.8 修訂
3HP的肝毒性 0.4% 應該是引用最下面那篇美國的研究報告
3HP藥物相關的肝炎(沒有症狀但有定時抽血)約 1.5%
因使用3HP發生肝炎而永久停藥的機率約千分之1
造成永久停藥之不良反應. 佔整體服藥民眾的比率分別為發燒 3.5% 、皮膚癢疹2.2%、頭暈2.1%及嘔吐1.9%
造成永久停藥之不良反應可能在第三次至第十次服藥後發生,最常見症狀是: 冒冷汗、喘及胸悶或腹痛. 緩解時間約 6-48 小時. 之後並無後遺症或死亡案例報告.
3HP最常見的副作用並非肝炎




四、副作用
不論 PREVENT TB Trial、台灣的本土研究 5,6,12或全國速克伏副作用藥物安全監測結果皆顯示,3HP 的肝毒性明顯較低於 9H。在 PREVENT TB Trial 與藥物相關的肝炎發生比例,3HP 明顯地較 9H 來得低(0.4% vs. 2.7%),而造成永久停藥分別為 0.3-0.9%和 2-4.3%13。國內資料 5顯示,常規監測肝炎的情況下,與藥物相關的肝炎發生比例,3HP 較 9H 來得低(1.5% vs. 5.3%)。另依據全國監測資料 12,使用 3HP 個案因為肝炎永久停藥的情況為 0.6%,相較過去 9H 監測資料 14,<10 歲個案因為肝炎永久停藥的發生率為 1‰;20 歲達 1%;30 歲以上升為 2-4%,亦可得知成人使用 3HP 會因藥物造成的肝炎而永久停藥之情形明顯下降。
至於非因肝炎而導致永久停藥的其他副作用,依 PREVENT TB Trial 資料顯示 13,約 3.5%的病人有全身性藥物反應,其中 63%為類似流感之症狀(flu-likesyndrome),例如:頭暈、頭痛、噁心或嘔吐、肌肉痠痛、無力、疲倦、發燒、盜汗、呼吸急促、臉紅及寒顫等;這種情況在 9H 處方的發生率則相當低(0.4%有全身性藥物反應,其中 13%為 flu-like syndrome),上述各種不舒服若經過症狀治療與再確認,造成 3HP 和 9H 永久停藥之比率分別為 3.5%和 0.4%。此類全身性藥物反應副作用,多在短時間內可緩解,不影響服藥,較嚴重的全身性反應絕大多數發生在第三到第四個劑量。

國內資料 5 指出有 3.8%的病人有全身性藥物反應,其中 40.9%為 flu-like syndrome,10.6%為皮膚癢疹。另全國監測資料 12顯示,9.5%使用者會因不良反應永久停藥;30-49 歲女性較男性更容易因為服用 3HP 產生之不良反應永久停藥;年紀越大者副作用越多。造成永久停藥之不良反應,以發燒(37%)、皮膚癢疹(23%)、頭暈(22%)及嘔吐(20%)為最常見,這些不良反應佔整體服藥民眾的比率分別為 3.5%,2.2%,2.1%及 1.9%。觀察 4,721 位 3HP 服用者,因為服藥產生嚴重不良反應而需要住院或到急診留觀超過 24 小時者佔 7‰,其中一半的嚴重不良反應跟類流感症狀有關,18%與肝炎有關。

「速克伏」跟其他藥物一樣,亦可能有過敏反應的發生(例如:低血壓、蕁麻疹、血管神經性水腫、急性支氣管痙攣、結膜炎、血小板減少、中性球減少),其發生率<1%。如果發生過敏反應,建議停藥並視臨床需要給予支持療法 3,13。
在將近 4000 人的 PREVENT TB Trial3,13、300 多人在紐約市的經驗 15,以及美國 CDC 主導約 3500 人的上市後監測 16,並沒有死亡或因嚴重副作用導致殘疾的狀況發生。而國內監測資料12顯示,過敏反應導致永久停藥的機率約為1.3‰,初期的症狀可能是類流感或疲勞不適,不舒服症狀的發作時間一次比一次快速(可能一吃藥半小時內就發作),造成永久停藥之不良反應可能在第三次至第十次服藥後發生,以冒冷汗、喘及胸悶或腹痛為常見之臨床表現,患者至急診或住院時有血壓偏低、心跳快的情形,部分病患會抱怨似乎要昏過去的感覺,經給予輸液支持後症狀可獲得緩解,緩解時間從 6-48 小時不等。此類病患停藥後,未留下長期後遺症亦無死亡情形,與國外經驗相仿。

在 PREVENT TB Trial 的報告中指出,3HP 的使用個案中,有觀察到 6 名發生 syncope 的情況 (其中一名有喪失意識的情況,其餘皆無),但預後良好 13,另有系統性文獻回顧 17 估計發生率為 2‰。美國 CDC 發現,當服用 3HP 感染者有同時使用抗高血壓藥物或者中樞神經抑制劑 (如:三環抗憂鬱劑或者安眠藥),較容易有此類情形發生,但原因不明 16。由於在臨床試驗時也觀察到部分個案有低血壓的情形,可能在同時使用上述藥物的病人,血壓的控制會比較差,因此建議同時服用 3HP 與上述藥物的個案,服完 3HP 的 2-6 小時,在變換姿勢時,請減緩速度以避免姿勢性低血壓的產生。


五、如何監測及處置副作用 由於「速克伏」是由 INH 與 RPT 組成,在副作用上,肝炎及全身性不適仍 然是需要重視的。治療潛伏結核感染時,仍須留意肝炎的副作用。即使 3HP 較 9H 更少發生藥物性肝炎,治療期間的肝炎副作用監測,原則上比照 9H 處方在 現行結核病診治指引之建議,評估病患是否有潛在性肝病或其他可能引起肝炎的 狀況來決定,請參照附件二:潛伏結核感染治療之肝功能監測流程。與 9H 不同 的地方是,在慢性肝病或者有其他醫療的考慮(貧血或血小板相關的疾病)時, 需要抽驗 CBC/DC 的基礎值,再決定追蹤的頻率。「速克伏」治療期間需要每月 回診,若發生肝炎,3HP 停藥的原則請參照 9H 處方建議。其餘非過敏反應的副 作用,則視臨床需要給予支持療法,停藥與否視個別病人是否能接受及臨床嚴重 度而決定。 從文獻可知,使用 3HP 最常遇到的副作用還是非肝炎之其他副作用,例 如: 疲倦、噁心、頭痛、無力等,故用藥前適當的說明 (可利用速克伏短程治療 處方用藥須知 18),搭配都治關懷,協助支持個案,對於完成治療是相當重要 的。如果發生過敏反應,則建議停藥並視臨床需要給予支持療法。若遇到發燒 等 flu-like syndrome,最可能的還是 3HP 的副作用,經驗上可先確認病人是 否在服藥後幾小時發生,一天內即緩解,那表示藥物相關的機會最大。若非上 述之典型症狀,鑑別診斷是否有其他發燒的疾病,例如流感、泌尿道感染等, 再依各疾病對症治療。預先讓病人知道可能的 flu-like syndrome,開立解熱鎮痛劑(例如: Acetaminophen),讓病人碰到發燒先觀察反應,而不是跑急診。 部分病人噁心嘔吐厲害,可使用服藥前止吐劑,來緩解服藥當下的不適。若遇 到肝炎,依 9H 停藥標準處理,原則上不再以同樣的處方重新試藥(rechallenge)。出現其他的副作用,可考慮 re-challenge,若失敗亦可考慮轉換 成 9H。但切記,病人的意願最重要,當出現太嚴重的副作用,例如:acute renal failure, hemolytic anemia, thrombocytopenia, anaphylaxis—包括 wheezing 或 dyspnea,re-challenge 可能就較不適合。Re-challenge 3HP 的間隔建議要相隔 24 小時以上,流程圖請參照附件 3 13。 當使用 3HP 遇到副作用,醫療人員需要溝通討論時,可透過 1922 反映, 本署防疫醫師會主動與您聯繫,協助解決相關問題。疾病管制署亦會建立合作醫 師電子郵件群組,定期發送相關訊息。在計畫推動初期定期舉辦電話會議,並邀 請專家們列席,讓醫師及個管師自由參加提問討論。

下面這篇是美國的統計報告
3HP 相較於其他處方. 肝毒性較低. 大約千分之四.

總共6862名接受治療的患者, 其中 77 人( 1.1%)發生肝毒性.
52人 (0.8%) 有症狀
61名(1.8%)發生在使用9H處方患者
15名(0.4%)發生在使用 3HP 患者
Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI

RESULTS
Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors.

2023年7月26日 星期三

潛伏型結核感染LTBI-治療造成的不良反應

023-07-27 11:05 
高達 10% 的TB可能有抗藥性
台灣的TB治療會例行進行培養.
Smear positive 的患者. 三周會通常培養會出現陽性
WHO建議加入 FQ 一起治療, 但台灣的情況跟外國不太相同
LTBI 完成治療之後的保護力有 9 成(所以用藥後不一定能根治TB)
萬一指標個案被排除TB診斷. 接觸者IGRA陽性仍代表曾感染過結核菌(感染源非指標個案). 還是建議完成3HP治療. 除非已經發生肺結核, 或五歲以下兒童, 暴露滿八周之後檢測是陰性. 才停止治療. 

下面資料來自結核病防治指引第十章 潛伏結核感染(LTBI)診斷與治療
嚴重不良反應定義為死亡、住院或急診留觀超過24小時
兩萬八千多人之中, 大約 2% 因藥物不良反應而永久中斷治療
年齡大的群體, 因不良反應停藥機率更高(40-69歲 > 6%)
有肝炎症狀且 GPT> 3倍正常值(或無症狀 GPT>5倍正常值) 約 1%
因肝炎需住院約 千分之 0.6
無死亡個案
小孩發生的副作用主要是癢
13歲以上發生的副作用主要是肝炎(3HP和4R 肝炎機率相對較低) 
4R 嚴重肝炎 0.3%, 兒童不良反應機率 < 5%. 皆為 1級或2級不良反應, 副作用停藥率 2%, 因肝炎永久停藥 0%
9H 嚴重肝炎 1.8%, 兒童不良反應機率 < 5%. 皆為 1級或2級不良反應. 副作用停藥率 12%. 因肝炎永久停藥 8%
3HP 副作用機率 21% 全身性副作用 3.5%, 因副作用永久停藥 4.9%, 完成治療比例 82%, 老年人發生副作用機率並不會增加, 但老年人因副作用放棄治療機率比較高(老人耐受性較低)




臺灣矯正機關執行 4R 與 6H 的 安全性比較也顯示,因為副作用停藥的比例 4R 明顯較低(2% vs. 12%),且因為肝 炎造成的永久停藥更是懸殊 (0% vs. 8%)。在 2017 年系統性回顧及統合分析也顯 示,不論是只有 RMP 的處方或者是 3HP,肝毒性都比 6H 或 9H 的肝毒性,統計顯著來得低。3HR 沒有直接與 6H 或 9H 比較的資料,但知道肝毒性比 12H 要來 得低。 由於僅一篇於 2019 年發表的隨機分派臨床試驗報告,愛滋感染孕婦在產後 3 個月內使用 INH 治療,有較高的肝炎風險(6.6%),本指引建議,產婦在產後 3 個月 接受 LTBI 治療期間,請特別注意肝功能變化。基於前篇報告,世界衛生組織進行系統性文獻回顧,在 2020 年指引中指出,懷孕期間接受 LTBI 治療並不會造成胎兒 或新生兒死亡、早產、低出生體重或先天畸形等不良的結果,且孕期間 LTBI 治療導致第三級或第四級肝毒性並沒有顯著差異,除非有特殊狀況,無須定期檢驗肝功能。


10.2.5 不良反應的發生
使用 9H 處方,發生不良反應的風險隨年齡增加,自 2008 年 4 月 1 日起到 2014 年 9 月 30 日期間,由結核病追蹤管理系統中,下載在這段時間登記並開始接受 LTBI 治療的 28,353 位個案。約有 2%的 LTBI 治療個案因為不良反應而永久中斷,其中 40-69 歲的中高齡族群,有超過 6%的發生率。

肝炎(ALT [GPT]>正常值 5 倍或臨床有肝炎症狀且 ALT[GPT]>正常值 3 倍)造成永久停藥有 1%。

以年齡 層分析,20 歲以下發生率非常低,小於 0.3%;超過 30 歲發生比例超過 2%,主要 是 60-69 歲年齡層的發生率最高達 4%。因肝炎導致住院比例為 0.6‰ (16/28,353),沒有觀察到死亡個案。不良反應的種類,依年齡有所不同,若依<13 歲、13-29 歲及 30 歲以上分層來看,導致永遠停藥的不良反應,13 歲以上 2 個年齡層最常見都是肝炎及嚴重肝炎(分別為 56%、68%),其次是皮膚癢或起疹子(分別 為 13%、9%);而<13 歲則以皮膚相關癢疹為最多(53%),肝炎及嚴重肝炎占 20%。 Dick Menzies 等人於 2018 年,發表跨國隨機分派臨床試驗,4R 與 9H 的治 療發生非懷孕的第 3 至 5 級不良反應比例,分別為 0.8% vs. 2.2%,而嚴重肝炎的 發生情形,分別為 0.3% vs. 1.8%,皆以 4R 較安全。兒童的部分亦顯示,2 種處 方整體不良反應<5%且皆為 1 至 2 級不良反應。臺灣矯正機關執行 4R 與 6H 的 安全性比較也顯示,因為副作用停藥的比例 4R 明顯較低(2% vs. 12%),且因為肝 炎造成的永久停藥更是懸殊 (0% vs. 8%)。在 2017 年系統性回顧及統合分析也顯 示,不論是只有 RMP 的處方或者是 3HP,肝毒性都比 6H 或 9H 的肝毒性,統計顯著來得低。3HR 沒有直接與 6H 或 9H 比較的資料,但知道肝毒性比 12H 要來 得低。 由於僅一篇於 2019 年發表的隨機分派臨床試驗報告,愛滋感染孕婦在產後 3 個月內使用 INH 治療,有較高的肝炎風險(6.6%),本指引建議,產婦在產後 3 個月 接受 LTBI 治療期間,請特別注意肝功能變化。基於前篇報告,世界衛生組織進行系統性文獻回顧,在 2020 年指引中指出,懷孕期間接受 LTBI 治療並不會造成胎兒 或新生兒死亡、早產、低出生體重或先天畸形等不良的結果,且孕期間 LTBI 治療導致第三級或第四級肝毒性並沒有顯著差異,除非有特殊狀況,無須定期檢驗肝功能。

美國 CDC 的臨床試驗 TBTC 26 顯示,3HP 與藥物相關的肝炎發生比例明顯較9H 低(0.4% vs 2.7%);臺灣 2014 年至 2016 年收案 263 人的研究也顯示同樣的結果(3HP 1.5% vs. 9H 5.3%)。另依據全國監測資料(表 10-3),使用 3HP 及 4R 個案因為肝炎達 5 倍 GPT 上升而導致永久停藥的情況,與 9H 比起來,不論哪個年齡層都是顯著較低。TBTC 26 試驗中,3HP 和 9H 分別有 21%和 14%個案有副作用的問題,多在短時間內可緩解,不影響服藥。最終因為副作用造成永久停藥分別為 4.9%和 3.7%,完成治療的比例則為 82% 和 69%。值得注意的是,在 3HP 分組中有 3.5%的病人有全身性藥物反應,在這些全身性藥物反應的病人中,最常遇到的不良反應(63%)為類似流感相關症狀(flu-like syndrome),例如:頭暈、頭痛、噁心或嘔吐、肌肉痠痛、無力、疲倦、發燒、盜汗、呼吸急促、臉紅及寒顫等症狀(本文全身性藥物反應 flu-like syndrome 之定義是,有四種症狀嚴重程度達到二級以上);這種情況在 9H 處方的發生率相當低(僅 0.4%有全身性藥物反應,其中 13%為類似流感之症狀),其他較少見的全身性藥物反應不良反應,包括有急性過敏性休克反應,例如皮疹類,腸胃道和呼吸道等分類。較嚴重的全身性反應絕大多數發生在第 3 個到第 4 個劑量。在 PREVENT TB 臨床試驗(將近 4,000 人),紐約市(300 多人),以及美國 CDC 主導的上市後監測(約 3,500 人),並沒有因為 3HP 死亡或因嚴重不良反應導致殘疾的狀況發生。

3HP 的弱點在於「非」肝炎之副作用,我國 2014-2016 年收案 263 人的臨床試驗結果顯示,服用 3HP 約有 41%的病人抱怨有任何一種類流感症狀,皮疹約有11%,相較於 9H 此兩項不良反應的比例為 17%和 7%,雖然藥物不良反應而停藥的比例 3HP 高於 9H (9% vs. 5%),全身性的過敏反應,亦是 3HP 高於 9H(4% vs. 0%),與美國的 PREVENT TB Trial (TBTC26)有類似的結果,且女性較男性容易產生發燒不適的情況(14% vs. 1%),但最終停藥的比率分別為 11%與 22%,3HP 明顯較 9H 來得容易完成治療。那些因為副作用而導致停藥的個案被發現的症狀往往是發燒,症狀發生的中位數為 15 天(四分位 13.3-23.8)。

由此可知,在病人治療的過程中,提供足夠的衛教和支持(例如:醫師診間衛教及適時適當的提供藥物緩解,藥局提供病人用藥須知及提醒,醫院及公衛個管充分掌握病人副作用及藥物交互作用的可能並安排回診,關懷員提供以病人為中心的都治計畫,配合病人可以服藥的時間進行都治關懷以協助定時服藥),是克服副作用和提高完治率的不二法門。國內也有研究顯示,高齡的病人接受 3HP 治療,並不會有較高比例發生副作用,但是一旦發生副作用較不容易耐受,較容易放棄治療。全國推動 3HP 治療後蒐集 2016-2019 年間,13,427 位接受 3HP 治療的 LTBI 接觸者資料,多變項分析結果顯示年齡越大、女性、指標來自非高風險地區者,因 3HP 不良反應導致永久停藥的機會越大。其中,女性比同齡男性更容易發生因為不良反應而永久停藥的情況,在 18-64 歲的年齡層達到統計顯著的差異。此外,透過勾稽健保資料庫觀察此群接觸者的共病情況,可以發現糖尿病、需定期血液透析、慢性腎衰竭、慢性肝病、使用類固醇超過 28 天等共病接觸者,皆較沒有共病接觸者有更高的風險因不良反應而永久停藥,藥物間交互作用可能是有共病的中高年齡病人完治率較低的主要原因。此外,國內全國性監測資料顯示,達到嚴重不良反應(定義為死亡、住院或急診留觀超過24小時)而永久停止服用 3HP 的個案中,54 位以過敏反應來表現,故符合嚴重不良反應造成永久停藥的過敏反應,發生機率約為 4‰。其中有 87%同時合併有類流感症狀,48%診斷過敏的依據是低血壓(其中的 46%同時合併呼吸道過敏症狀:胸悶、胸痛、心搏過速等症狀),另外 24%僅有呼吸道過敏症狀,沒有低血壓。起初的症狀可能是類流感或者疲勞不適、頭暈等,每次不良反應出現的時間,在服藥後有提早的趨勢,但 96%都發生在服藥後的 24 小時內。產生嚴重不良反應的時間從第 2 劑到第 9 劑不等(但 75% 發生在前 4 個劑量之內),中位數為服完第 3 劑。這些過敏個案,近 9 成有類流感症狀(flu-like syndrome),約 5 成有低血壓,臨床上需要尋找可能的感染源及處理敗血症休克,若病人出現肋膜積水,常會被認為是肺炎,此外被診斷為泌尿道感染併敗血症也是常見的診斷,除了抗生素以外也必須補充液體,以及注射抗組織胺、類固醇、甚至升壓劑等,才能迅速穩定病情。在 54 位符合嚴重不良反應造成永久停藥的過敏反應個案中,有 3 位病人抱怨有快要昏過去的感覺;大部分個案經給予輸液後症狀緩解,緩解時間需約從 6-48 小時不等。比較特別的是,部分病人甚至出現胸痛、冒冷汗或心搏過速等心肌梗塞症狀,有 3 位個案(42 歲男性和66歲女性及72歲男性),雖然沒有出現典型的心電圖變化或心肌酵素CK/CKMB/Trponin I 僅輕微上升,但因臨床懷疑心肌梗塞,施行心導管檢查並確認排除血管堵塞情況,且症狀迅速消失。另有 52 歲與 90 歲兩位男性,因嚴重不良事件而被臨床懷疑肺栓塞,並以電腦斷層掃描診斷,也都復原迅速,但與 3HP 處方之因果關係不明。長期觀察有過敏反應的病人於停藥後,並未留下長期後遺症亦無死亡情形,與國外文獻如美國 CDC 上市後追蹤及紐約市的公衛田野觀察相仿。在過敏反應後,少數病人仍願意將處方轉換成 9H 以 INH 300mg 治療,少於一半的病人可以耐受;也就是說,至少將近 6 成的過敏,一服用 INH 就觀察到類似3HP 服用後的全身性反應,此過敏可能跟 isoniazid 有關,而非僅與 rifapentine相關而已。這也可以解釋為何在台灣進行 1HP 的臨床試驗時,由於每日的 INH 劑量 300mg 僅每週 3HP 時的 INH 900mg 的 1/3 劑量,觀察服用 1HP 約有 3.4%的病人抱怨有任何一種類流感症狀,皮疹約有 6.3%,與 3HP 有顯著的不同;1HP 處方組血中 RPT 濃度明顯高於 3HP 組,故推測產生的副作用大多以蕁麻疹、皮疹為主,與 3HP 以類流感症狀為主的副作用有所差異。故未來將依照病人體內藥物濃度或者代謝基因例如 NAT2 gene 等方向,繼續進行深入研究來探討造成過敏性反應的原因為何。此外,我國 2-17 歲兒童的安全性報告顯示,不論是 3HP或 9H 因副作用造成永久中斷的比例皆<2%,該等處方在兒童相對安全,也容易接納。

近年美國 FDA 及歐盟 EMA 陸續發布有關 FQ 藥品可能潛在有「肌腱炎、肌腱斷裂等」、「中樞神經系統不良反應,包括精神相關不良反應、癲癇等」及「低血糖」等嚴重不良反應的風險,再加上國際和國內,MDR-TB 個案在治療多種藥物組合處方(含 FQ)時,有心電圖 QTc 延長的經驗。建議在臨床上除了提供基礎及後續追蹤的血糖值,肝功能及心電圖,並衛教病人,服藥後若出現不適症狀(如胸悶或心臟亂跳等) 或者骨骼肌肉問題 (肌腱、關節或肌肉疼痛等),精神或行為改變 (失眠、意識混亂、幻覺、記憶問題等),請病人立即告知醫療人員來評估是否繼續服藥。下列的病人要特別注意服藥期間的不良反應監測,包括: 年紀大於 60 歲、腎臟功能不良、曾經接受器官移植或是同時使用類固醇藥品者,可能較容易在使用FQ 後發生關節疼痛腫脹或肌腱傷害,另外,同時服用降血糖藥或施打胰島素的糖尿病患者,除監控病人的血糖,確保病人了解低血糖可能的症狀及處置方式,及若出現上述情況,請告知醫療人員。

LTBI 感染者完成治療才能提供完整(約 9 成)的保護發病效果,因此對於曾接受過治療,但因故中斷治療者,建議臨床醫師及公衛護理師向 LTBI 個案衛教,如當初中斷治療原因消失或改善,再次評估排除活動性結核病後應接續(或重新,沒有硬性規定)給予一個完整的治療療程;另過去政策接觸者治療時,倘指標個案排除結核病診斷,該接觸者 LTBI 治療可能被中斷,考量該接觸者 LTBI 檢驗陽性代表曾經遭受結核菌感染,因此建議,只要排除發病、或未滿 5 歲兒童與指標個案終止有效暴露滿 8 週之 LTBI 檢驗結果為陰性需中斷治療外,請協助個案直至完成治療。

10.2.6 如何監測及處置不良反應
個案治療期間需要每月回診,依臨床問診及身體健康檢查,來決定是否懷疑肝炎及是否需要進行肝指數的檢驗。依照 9H 所設計的 LTBI 治療之肝功能監測流程如下,若病人追蹤期間肝功能狀況達符合肝炎,則建議停藥。由於 3HP/3HR/4R 在治療 LTBI 時,肝炎的不良反應發生率更低,故此流程應已足夠。若 LTBI 治療過程發生定義肝炎的程度,建議先停藥衛教病人,了解病人是否有其他肝炎的風險並予以治療(例如慢性病毒性肝炎),給予支持療法,通常 2 週後

肝指數會下降 1/2,若臨床上沒有不舒服或危險因子,可以 2 週甚至 1 個月後再追蹤,直到回到正常值上限的 2 倍之內即可。全身性不適等藥物相關的過敏反應仍然是需要重視的,若符合過敏定義,「不」建議進行同樣處方的 re-challenge(可以嘗試轉換其他處方)。其餘非過敏反應的不良反應,則視臨床需要給予支持療法,停藥與否視個別病人是否能接受及臨床嚴重度而決定。

由於 3HP/3HR/1HP 是由 INH 與 RPT/RMP 組成,與 4R 含有 RMP 一樣,極少數可能有骨髓抑制的情況,故當病人有肝病或其他醫療考慮如貧血或血小板相關問題,建議在用藥前檢驗CBC/DC 基礎值,再決定治療中的追蹤方式及頻率。

使用 3HP 最常遇到的不良反應是非肝炎之其他不良反應,例如:疲倦、噁心、頭痛、無力等,故用藥前適當的說明(可利用 3HP 處方治療用藥須知),搭配都治關懷,協助支持個案,是相當重要的。如果發生過敏反應,則建議停藥並視臨床需要給予支持療法。若遇到發燒等類流感症狀,最可能的還是 3HP 的不良反應,經驗上可先確認病人是否在服藥後幾小時發生,一天內即緩解,那表示藥物相關的機會最大。預先讓病人知道可能的類流感症狀,開立解熱鎮痛劑(例如普拿疼),讓病人碰到發燒先觀察反應,而不是跑急診。部分病人噁心嘔吐厲害,服藥前可使用止吐劑,來緩解服藥當下的不適。更多有關 3HP 的臨床處置細節以及可能和病人其他慢性疾病用藥產生藥物交互作用,請參考[速克伏處方使用臨床建議],[3HP處方治療用藥須知]單張 (傳染病與防疫專題/傳染病介紹/第三類法定傳染病/結核病/治療照護/潛伏結核感染專區)。

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